In diagnostic imaging modalities, such as X-ray, MR and ultrasound, the use of contrast agents to enhance image contrast, e.g. between different organs or tissues or between healthy and unhealthy tissue, is a well established technique.
In MR imaging, the contrast agents used generally have a contrast generating effect due to their effects on the characteristic relaxation times T.sub.1 (spin-lattice) or T.sub.2 (spin-spin) of the imaging nuclei which are responsible for the MR signals which are detected and manipulated to yield images.
In T.sub.1 and T.sub.2 dependant images, the function for signal intensity is dependent on T.sub.1 in such a way that, absent other effects, a decrease in T.sub.1 would lead to an increase in signal intensity. However the signal intensity function is dependent on T.sub.2 in such a way that, again absent other effects, a decrease in T.sub.2 (or T.sub.2 *) would lead to a decrease in signal intensity.
For the purposes of this specification references to T.sub.2 and T.sub.2 dependency shall where appropriate cover T.sub.2 * and T.sub.2 * dependency as well.
Thus, while MR contrast agents may reduce both T.sub.1 and T.sub.2, for a given imaging sequence one effect may dominate, and where the T.sub.1 decrease dominates the agent may be referred to as a T.sub.1 or positive contrast agent while where the T.sub.2 decrease dominates the agent may be called a T.sub.2 or negative contrast agent.
The first parenteral MR contrast agents available commercially were low molecular weight lanthanide chelates, such as GdDTPA and GdDTPA-BMA, which distribute extracellularly and generally have an MR signal intensity increasing effect in the zones into which they distribute. Such contrast agents are thus commonly used in T.sub.1 -weighted imaging sequences in which their image brightening effect is optimal.
Later, the use of magnetic particles (e.g. superparamagnetic iron oxide particles) as T.sub.2 or negative agents for investigation of the liver was proposed in view of the ability of the organs of the reticuloendothelial system (RES) to abstract particulate materials from the blood. Thus, for example, the use of magnetic particles in T.sub.2 -weighted imaging of the liver and spleen was proposed in U.S. Pat. No. 4,849,210 (Widder). Widder taught that the particle should be administered and allowed to accumulate at the liver before a T.sub.2 -weighted imaging sequence is used to generate images in which the particles, localized image darkening effect serves to enhance contrast, for example between healthy liver parenchyma and liver tumour tissue.
Recently there has been much interest in the development of MR contrast agents which assist visualization of the vasculature, i.e. so-called blood pool or angiographic contrast agents, by enhancing contrast between blood vessels and surrounding tissue or organs. The utility of an MR angiographic contrast agent depends largely upon its relaxivity profile and pharmacokinetic behaviour. Ideally the agent should remain in the intravascular space for a period of time sufficient to allow image generation, i.e. the blood half life should be sufficient to provide an adequate imaging window. For this purpose the low molecular weight chelates are inadequate because of their rapid distribution to the whole extracellular volume.
Macromolecular paramagnetic agents (e.g. lanthanide chelates of polychelants) have been found to be operable as MR angiographic contrast agents but only have the contrast enhancing effect of brightening blood vessels.
It has now been found however that certain magnetic particles having low r.sub.2 /r.sub.1 ratios (i.e. ratios of T.sub.2 relativity to T.sub.1 relativity) may be used particularly effectively in liver angiography, the study of the vasculature within the liver in RES angiography (or the study of other phagocytosing organs which have appropriate vasculature), by virtue of their opposed contrast generating effects in the two environments of blood vessel (before RES uptake) and liver tissue (after RES uptake). Using a T.sub.1 -weighted imaging sequence, a positive signal enhancement of the vessels containing the magnetic particles is achieved whereas in the organs of the reticuloendothelial system, once the particles accumulate, there is a negative contrast effect. Thus the vessel to liver contrast is increased significantly.
To achieve this double contrast effect, it is important that the magnetic particles used as the contrast agent should comprise particles which, unlike those of Widder (supra) or of other commercially available magnetic particle MR contrast media, have a low r.sub.2 /r.sub.1 ratio and a prolonged blood residence half-life and that the images generated should comprise (i.e. be or include) T.sub.1 -weighted images.